title: Two structural and functional domains of MESD required for proper folding and trafficking of LRP5/6.
abstract: How the endoplasmic reticulum (ER) folding machinery coordinates general and specialized chaperones during protein translation and folding remains an important unanswered question. Here, we show two structural domains in MESD, a specialized chaperone for LRP5/6, carry out dual functions. The chaperone domain forms a complex with the immature receptor, maintaining the β-propeller (BP) domain in an interaction competent state for epidermal growth factor-repeat binding. This promotes proper folding of the BP domain, causing a binding switch from the chaperone domain to the escort domain. The escort complex ensures LRP5/6 safe-trafficking from the ER to the Golgi by preventing premature ligand-binding. Inside the Golgi, the BP domain may contain a histidine switch, regulating MESD dissociation and retrieval. Together, we generate a plausible cell biology picture of the MESD/LRP5/6 pathway, suggesting that it is the specialized chaperones, MESD, that serves as the folding template to drive proper folding and safe trafficking of large multidomain proteins LRP5/6.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Jianglei
authors.initials: J
authors.lastname: Chen
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Nowak
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006056:Golgi Apparatus / Q000378:metabolism; D006639:Histidine / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C506348:MESD protein, human; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D006639:Histidine; D004815:Epidermal Growth Factor